Traumatic brain injury (TBI) triggers delayed biochemical changes, including chronic neuroinflammation, that contribute to tissue loss and neurological deficits. Similar to clinical TBI, we have shown that M1 (neurotoxic) microglia are chronically active for months-to-years following experimental TBI, contributing to progressive neurodegeneration. Our group was the first to demonstrate the ability of conventional orthosteric mGluR5 metabotropic glutamate receptor 5 (mGluR5) agonists to attenuate miR-155, a key M1-inducing microRNA (miR), negatively regulate the M1 phenotype, limit chronic microglial activation and reduce progressive neuronal loss, even when administered centrally at one month after TBI. Importantly, mGluR5 positive allosteric modulators (PAMs) not only attenuate M1 but also promote M2 (neuroprotective) microglia phenotypes after TBI. This is accomplished by combined action on key microRNA modulators of neuroinflammation, down-regulating miR-155 and up-regulating the M2-inducing miR-124. There is an urgent unmet need to identify selective targeted therapies to limit posttraumatic inflammatory neurodegeneration. Our central hypothesis is that selective mGluR5 PAMs have superior therapeutic effects than orthosteric agonists on neuroinflammation/neurodegeneration by concurrently attenuating both TBI-induced chronic M1 responses and promoting neuroprotective M2 responses; molecular interventions that target the underlying mechanisms and tip the miR-155/miR-124 balance in favor of miR-124 are neuroprotective. These hypotheses are supported by strong preliminary studies showing that mGluR5 PAMs lower miR-155, increase miR-124, reverse M1/M2 imbalance, as well as attenuate neuronal loss and neurological impairments following TBI. The proposed specific aims are: 1) Define the specific mGluR5 PAM (VU0360172) signaling intermediaries that are responsible for down-regulating M1 and up-regulating M2 microglia; 2) Determine the neuroprotective effects of delayed systemic treatment with mGluR5 PAMs on TBI-induced chronic neuroinflammation, progressive neurodegeneration and associated neurological impairments; and 3) Determine the neuroprotective effects of delayed molecular interventions targeting miR-155/-124 on TBI-induced chronic neuroinflammation, progressive neurodegeneration and associated neurological impairments. These aims should support the following expected outcomes: neuroprotective effects of mGluR5 PAMs after TBI reflect, in part, reversing posttraumatic miR-155/miR-124 changes; that mGluR5 PAMs have robust neuroprotective effects even with delayed systemic administration; and that combined molecular modulation of miR-155 (down-regulation) and miR-124 (up-regulation) after TBI have additive neuroprotective effects. We expect to have an important positive impact by demonstrating the pathophysiological mechanisms underlying progressive neurodegeneration after TBI, and providing experimental support for late therapeutic interventions that alter M1/M2 balance.